Heritable Variants in the Chromosome 1q22 Locus Increase Gastric Cancer Risk via Altered Chromatin Looping and Increased UBAP2L Expression
Heritable Variants in the Chromosome 1q22 Locus Increase Gastric Cancer Risk via Altered Chromatin Looping and Increased UBAP2L Expression
复制标题
染色体 1q22 位点的遗传变异通过改变染色质环和增加 UBAP2L 表达增加胃癌风险
DOI：
10.1158/1541-7786.mcr-21-0001
复制
发表时间：
2021-12-01
影响因子：
5.2
通讯作者：
Sun, Yujie
中科院分区：
文献类型：
--
作者：
Guan, Wei;Yang, Nan;Sun, Yujie
全基因组关联研究（GWAS）表明1 q22胃癌风险位点与疾病有关，但对其潜在的致癌功能知之甚少。本研究系统研究了1 q22区域rs 2075570（C>T）单核苷酸多态性与胃癌风险相关的生物学意义和潜在机制。我们在rs 2075570的64.8 kb高连锁不平衡块中的活性增强子中鉴定了两个功能性种系变异（rs 2049805-C和rs 2974931-G）。该增强子通过染色质成环上调泛素相关蛋白2样（UBAP 2L）基因表达超过960 kb的距离。胃癌组织中UBAP 2L的表达水平显著高于配对的非癌组织，且UBAP 2L的表达与患者的生存率呈负相关。下调UBAP 2L在体外和异种移植小鼠模型中抑制人胃癌细胞的增殖和侵袭。值得注意的是，这两种突变变异显著增强了增强子活性和UBAP 2L表达。总之，这项研究揭示了两个因果变化，在1 q22区域使用tag-SNP rs 2075570作为遗传标记。这些变异可能通过增强1 q22-Enh增强子调控的UBAP 2L靶基因的表达而影响胃癌的发生和发展。
Genome-wide association studies (GWAS) have implicated the 1q22 gastric cancer risk locus in disease, but little is known about its underlying oncogenic functions. This study represents a systematic investigation of the biological significance and potential mechanism associated with the gastric cancer risk of SNP rs2075570(C>T) in 1q22. We identified two functional germline variations (rs2049805-C and rs2974931-G) in an active enhancer in a 64.8 kb high-linkage disequilibrium block of rs2075570. The enhancer upregulated ubiquitin associated protein 2 like (UBAP2L) gene expression over a 960 kb distance by chromatin looping. Gastric cancer tissues expressed significantly higher levels of UBAP2L than was observed in the matched noncancerous tissues, and the UBAP2L expression was negatively correlated with patient survival. Downregulation of UBAP2L inhibited the proliferation and invasion of human gastric cancer cells in vitro and in a xenograft mouse model. Notably, the two mutant variations significantly enforced the enhancer activity and UBAP2L expression. In conclusion, this study revealed two causal variations in the 1q22 region using tag-SNP rs2075570 as a genetic marker. These variations may affect the occurrence and progression of gastric cancer by reinforcing the expression of the 1q22-Enh enhancer-regulated UBAP2L target gene.